Pyridines. Pyridine is the simplest heterocycle of the azine type. It is derived from benzene by replacement of a CH group by a N-atom.

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1 Pyridines Pyridine is the simplest heterocycle of the azine type. It is derived from benzene by replacement of a CH group by a N-atom. 88

2 The structure of pyridine is completely analogous to that of benzene, being related by replacement of CH by N. The key differences are: I. The departure from perfectly regular hexagonal geometry caused by the presence of the hetero atom, in particular the shorter carbon-nitrogen bonds, II. The replacement of a hydrogen in the plane of the ring with an unshaired electron pair, likewise in the plane of the ring, located in an sp 2 hybrid orbital, and not at all involved in the aromatic p-electron sextet; it is this nitrogen lone pair which is responsible for the basic properties of pyridines, and 89

3 III.A strong permanent dipole, traceable to the greater electronegativity of the nitrogen compared with carbon. 90

4 The following reactions can be predicted for pyridines on the basis of their electronic structure: I. The heteroatom make pyridines very unreactive to normal electrophilic aromatic substitution reactions. Conversely pyridines are susceptible to nucleophilic attack. Pyridines undergo electrophilic substitution reactions (S E Ar) more reluctantly but nucleophilic substitution (S N Ar) more readily than benzene. II. Electrophilic reagents attack preferably at the N- atom and at the b-c-atoms, while nucleophilic reagents prefer the a- and c-c-atoms. 91

5 Reactions of Pyridine Electrophilic Addition at Nitrogen In reactions which involve bond formation using the lone pair of electrons on the ring nitrogen, such as protonation and quaternisation, pyridines behave just like tertiary aliphatic or aromatic amines. When a pyridine reacts as a base or a nucleophile it forms a pyridinium cation in which the aromatic sextet is retained and the nitrogen acquires a formal positive charge. 92

6 Protonation at Nitrogen Pyridines form crystalline, frequently hygroscopic, salts with most protic acids. Nitration at Nitrogen This occurs readily by reaction of pyridines with nitronium salts, such as nitronium tetrafluoroborate. Protic nitrating agents such as nitric acid of course lead exclusively to N-protonation. 93

7 Acylation at nitrogen Acid chlorides and arylsulfonic acids react rapidly with pyridines generating 1-acyl- and 1- arylsulfonylpyridinium salts in solution. 94

8 Alkylation at nitrogen Alkyl halides and sulfates react readily with pyridines giving quaternary pyridinium salts. 95

9 Electrophilic substitution at Carbon atoms of the pyridine ring Electrophilic substitution of pyridines at a carbon is very difficult. Two factors seem to be responsible for this unreactivity: I. Pyridine ring is less nucleophilic than the benzene ring; nitrogen ring atom is more electronegative than carbon atoms and therefore it pulls electrons away from the carbon atoms inductively leaving a partial plus on the carbon atoms. 96

10 II. When pyridine compound is exposed to an acidic medium, it forms pyridinium salt. This increases resistance to electrophilic attack since the reaction will lead to doubly positive charged species. Less reactive than pyridine 97

11 When an electrophile attacks the pyridine ring, only position 3 is attacked. Why? Hint: draw resonance structures that result from electrophilic attack at various positions. The positive charge residing on an electronegative element with sextet configuration is unfavoured. 98

12 For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in conc. sulfuric acid) at 130 C. 99

13 Br Br N H S 3 Mechanism of bromination of pyridine 100

14 Pyridine can be activated to electrophilic substitution by conversion to pyridine-n-oxides. A series of preparatively interesting reactions on pyridine can be carried out by means of pyridine N- oxides such as the introduction of certain functions into the ring and side-chain which cannot be achieved in the parent system by direct methods. 101

15 The activating oxygen atom can be removed by reacting the pyridine N-oxide with phosphorous trichloride. 102

16 In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the opposite direction. Here, the resonance effect is more important, and electrophiles react at C-2(6) and C-4. 4 N

17 Thionyl chloride, for example, gives a mixture of 2- and 4-chloropyridine N-oxides in which the 4-isomer is predominant. PCl 3 Cl + N Cl N 104

18 However, pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then, on heating, to yield 2-acetoxypyridine through an addition-elimination process. 4 N 3 2 N 105

19 When a similar reaction is carried out upon the 2,3- dimethyl analogue, the acetoxy group rearranges from N-1 to the C-2 methyl group, at C, to form 2-acetoxymethyl-3-methylpyridine. N 106

20 H 2 Pd/EtH NH 2 N 107

21 Anion Chemistry of Pyridine H N H H N H Resonance stabilized The negative charge generated on the carbon goes to the electronegative nitrogen, which can better accommodate it. Works for 2(6)- and 4-alkylpyridines not for 3(5)-alkyl pyridines, why? 108

22 109

23 R Br N R 110

24 Another approach to electrophilic substitution involves the chemistry of 2-pyridone and 4- Pyridones which are obtained from the diazotization of the corresponding 2-aminopyridine and 4- aminopyridines, respectively. 111

25 Both pyridones can react with electrophiles at positions ortho and para to the activating oxygen atom. Reaction with phosphorous oxychloride gives chloropyridines. 112

26 Nucleophilic substituition of pyridine a) X=H b) X=Good leaving group X=H, Substitution with hydride transfer Nu: NaNH 2 - amination Nu: BuLi, PhLi etc - alkylation / arylation Nu: NaH - hydroxylation 113

27 At high temperature the intermediate anion can aromatize by loss of a hydride ion, eventhough, it is a poor leaving group. 114

28 b) X=LG, The nucleophilic substitution is much more facile when good leaving group such as X: Halogen (F>>Cl,>Br,>I), -S 2 R, -N 2, -R, are employed. 115

29 116

30 Cl SLW Nu N - H: is a bad leaving group 117

31 N Me N SPh N X N N Ph N NH 2 Me 118

32 Halogenopyridines can undergo metal-halogen exchange when treated with butyllithium. The lithium derivatives then behave in a similar manner to arylithiums and Grignard reagents and react with electrophiles such as aldehydes, ketones and nitriles. 119

33 N Me NaMe MeH N - N 2 Me N 120

34 121

35 SCH 402 Synthesis of Heterocycles Compounds :Nu (CH 2 )n (CH 2 )n Dr. Solomon Derese Nu Nu 122

36 SCH 402 Synthesis of Furan, Pyrrole and Thiophene Dr. Solomon Derese 123

37 SCH 402 Furans, pyrroles and thiophenes from 1,4-dicarbonyl compounds: Paal Knorr synthesis :Nu R 1 d + d + R 2 (CH 2 ) 2 :Nu = RNH 2, H 2 S Nu Dr. Solomon Derese 124

38 SCH 402 RNH 2 H Dr. Solomon Derese 125

39 SCH 402 Dr. Solomon Derese 126

40 Furans, pyrroles and thiophenes from 1,3-dicarbonyl (b-ketocarbonyl) compounds SCH 402 Base R 1 R 2 acidic hydrogens H enolate React with electrophiles Dr. Solomon Derese 127

41 Feist Benary synthesis of furans SCH 402 The Feist-Benary synthesis is an organic reaction between a-haloketones and b- dicarbonyl compounds to give substituted furans in the presence of base. R 1 + Et Na 2 C 3 R 1 Et X R 2 a-haloketones X = Cl, Br, I R 2 Dr. Solomon Derese 128

42 SCH 402 R 1 H Et R 2 Dr. Solomon Derese 129

43 130

44 Knorr-pyrrole synthesis SCH 402 This involves the condensation of a-amino ketones with a b-diketone or a b-ketoester to give a substituted pyrrole in the presence of a base like pyridine. a-amino ketones Dr. Solomon Derese 131

45 SCH 402 R 1 H Et H R 2 N H R 3 Dr. Solomon Derese 132

46 Fiesselmann synthesis SCH 402 1,3-Dicarbonyl compounds or b-chlorovinyl aldehydes react with thioglycolates or other thiols possessing a reactive methylene group to give thiophenes in the presence of pyridine. Dr. Solomon Derese 133

47 SCH 402 Dr. Solomon Derese 134

48 Synthesis of Pyridine SCH 402 R 1 R 2 1,5-Dicarbonyl compound :Nu = RNH 2 Dr. Solomon Derese 135

49 I. Reaction between a 1,5-diketone and ammonia Ammonia reacts with 1,5-diketones to give unstable 1,4-dihydropyridine, which can be easily dehydrogenated (using nitrobenzene or nitric acid) to give pyridine. 1,4-dihydropyridine 136

50 II. The Guareschi synthesis Unsymmetrical pyridines can be synthesised from a reaction between a b-dicarbonyl compound and a b- enaminocarbonyl compound or nitrile. 137

51 H H N H 138

52 139

53 III. The Hantzsch synthesis Symmetrical 1,4-dihydropyridines, which can be easily dehydrogenated (to form pyridines), are produced from the condensation of an aldehyde, ammonia, and two equivalents of a 1,3-dicarbonyl compounds (commonly a β-ketoester) which must have a central methylene. The product from the classical Hantzsch synthesis is necessarily a symmetrically substituted 1,4- dihydropyridine. Subsequent oxidation (or dehydrogenation) gives a symmetrical pyridine compound. 140

54 STEP I The reaction is believed to proceed via Knoevenagel Condensation. STEP II A second key intermediate is an ester enamine, which is produced by condensation of the second equivalent of the β-ketoester with ammonia: 141

55 STEP III Further condensation between these two fragments gives the dihydropyridine derivative: 142

56 143

57 H H NH 3 MECHANISM Ph H H H Ph H - H 2 Ph H - H 2 I NH 3 H NH 2 H NH 2 II 144

58 145

59 Nifedipine is in a group of drugs called calcium channel blockers. It works by N 2 relaxing the muscles of your heart and blood Me 2 C C 2 Me vessels. Nifedipine is used to treat hypertension (high blood pressure) and angina (chest pain). Me N H Nifedipine Me 146

60 C 2 Me Me NH 3 N 2 Me 2 C C 2 Me Me Me 147

61 XAZLE 148

62 IMIDAZLES THIAZLES 149

63 Diazepam (Valium) used for the treatment of anxiety disorders. Diazepam also is used for the treatment of agitation, tremors, delirium, seizures, and hallucinations resulting from alcohol withdrawal. It is used for the treatment of seizures and relief of muscle spasms in some neurological diseases Cl N Diazepam N 150

64 NaH (Aq) N NH Cl N NH 3 Cl Diazepam 151

65 Antifungal drug 152

66 N N NaN 2, HCl 0 o C N 153

67 F HN H N N N 154

68 Clopirac Nonsteroidal Antiinflammatory Drug) H H 3 C N C CH 3 Cl 155

69 H 3 C I N H H 3 C N CH 3 KH H 3 C N CH 3 C C Cl Cl 156

Chapter 5 N S. Typical Reactivity of Pyridines, Quinolines and Isoquinolines

Chapter 5 N S. Typical Reactivity of Pyridines, Quinolines and Isoquinolines Chapter 5 S Typical Reactivity of Pyridines, Quinolines and Isoquinolines 1 2 Typical Reactivity of Pyridines pyridines are much less susceptible to electrophilic substitution than benzene and much more